Cardiovascular abnormalities are significant manifestations of diabetes mellitus and account for much of the increased mortality in diabetic patients. It is well recognized that cardiomyopathy occurs frequently in diabetic patients in the absence of known cardiac risk factors. Although several mechanisms have been proposed, the pathogenesis of diabetic cardiomyopathy is not well understood, and the overall complexity of the disease suggests that additional regulatory mechanisms remain to be identified. Recently, a novel paradigm for the role of microRNAs (miRNAs) in cardiac function has emerged. Based on the profound influence of numerous miRNAs in the development of pathological cardiac hypertrophy and development, we hypothesize that diabetic cardiomyopathy is associated with alterations in specific miRNAs that contribute to the pathogenesis of the disease. Our recent work identified miR-152 to be significantly upregulated in human and rat diabetic failing hearts. It is therefore our hypothesis that miR-152 regulates genes involved in cardiac dysfunction associated with diabetic cardiomyopathy and silencing miR-152 in vivo can reserve such abnormalities. Our aim in this proposal is to identify, analyze and functionally elucidate the potential role of miR-152 and its physiological targets and signaling pathways in the setting of diabetes-induced cardiac dysfunction. Our long-term goal is to provide new approaches using miRNA-based therapeutics to treat heart failure in humans. The elucidation of how cardiac miRNAs expression contributes to the development of diabetic cardiomyopathy will be important to interfere with disease-related pathways and may prove valuable as potential therapeutics. PUBLIC HEALTH RELEVANCE: Diabetes is the world's fastest-growing disease with high morbidity and mortality rates, predominantly as a result of heart disease. Our recent work identified a set of microRNAs that are differentially altered in human and rat diabetic failing hearts; whether such dysregulation of microRNAs expression in the heart in response to diabetes contributes to the pathogenesis of the disease is currently unknown. Therefore, elucidating the role of microRNAs in the pathophysiological mechanisms underlying diabetic cardiomyopathy will help us devise new therapies aimed at stemming the tide of the epidemic of insulin resistance and its metabolic and cardiac complications.